In addition to their use as irreversible active site inhibitors of certain cysteine and serine-containing proteases (review: Demuth, J. Enzyme Inhibition, 1990, 3, 249), amino acid .alpha.-halomethyl ketones can be converted into N-protected amino acid epoxides, important intermediates for the synthesis of inhibitors of enzymes such as renin (Evans, et al., J. Org. Chem. 1985, 50, 4615; Luly, et al. J. Org. Chem. 1987, 52, 1487) and HIV protease (Handa, et al., EP 346847; Gordon, et al., published European patent application EP 580402). Standard methodology to prepare N-protected amino acid .alpha.-halomethyl ketones and alcohols (e.g. see Gordon, et al, EP 580402) involves initial treatment of N-protected amino acids I (Reaction Scheme 1) with an alkyl chloroformate, such as isobutyl chloroformate, and a tertiary amine, such as N-methyl morpholine, followed by addition of a diazomethane/diethyl ether solution to give an N-protected amino acid .alpha.-diazoketone II. ##STR1##
Treatment of II with a mineral acid such as HCl or HBr then gives the desired .alpha.-haloketone III. Intermediate III can be converted to epoxide IV by reduction with a hydride reducing agent such as NaBH.sub.4 and treatment of the resulting halohydrin with base, such as potassium hydroxide. As diazomethane is a hazardous reagent, methods to prepare compounds III which avoid the use of diazomethane would be advantageous. Kowalski et al. (J. Org. Chem. 1985, 50, 5140) have prepared .alpha.-bromoketones VII (Reaction Scheme 2) from ester (V) where R.sub.2 =aryl, heteroaryl, lower alkenyl, lower alkynyl, and lower alkyl (not including amino substituted alkyl) by treatment of the ester with 2 equivalents of the anion derived from dibromomethane, followed by addition of 1.5 equivalents of n-BuLi to the intermediate VI and hydrolysis.
When this method was used to convert aminoester (XI) to a halomethylketone (XIII) (see page 7 herein), the resulting yields were only modest.
It has since been surprisingly and unexpectedly found that replacement of the n-BuLi by an excess of the dihalomethane anion instead, specifically chloroiodomethane, results in greatly enhanced yields of 80% or more. ##STR2##
Barluenga, et al. (JCS Chem. Commun. 1994, 969) have prepared the .alpha.-chloroketone X (Reaction Scheme 3) from the .alpha.-amino ester VIII by treatment with 2 equivalents of the anion IX, generated from metallation of chloroiodomethane with methyl lithium in diethyl ether, followed by hydrolysis. Note that the anion IX is different than the anion XII (Reaction Scheme 4), generated from deprotonation of chloroiodomethane with a dialkylamide base such as LDA (i.e. lithium diisopropylamide amide), described in the present invention. Moreover, the Barluenga process has only been demonstrated for N,N-dibenzyl protected aminoester (Compound VIII). It is not clear that the process would work for N-carbamate protected aminoesters (Compound XI) as used herein. The Compounds XI are more easily prepared and deprotected if needed and allow for the presence of an active hydrogen in the nitrogen atom. Also, deprotonation of X.sub.1 CH.sub.2 X.sub.2 to form the anion X.sub.1 CH(Li) X.sub.2, which is our Compound XII, may be easier to carry out efficiently on a larger scale compared to transmetallation of ICH.sub.2 Cl to form the anion LiCH.sub.2 Cl (i.e. Compound IX) according to Barluenga. ##STR3##